The central theme of this project is to determine in a series of established human tumor cell lines how cytogenetic aberrations participate in the generation of acquired drug resistance. Three specific subprojects are proposed: 1) chromosome banding and in situ hybridization analysis of drug resistant compared to drug sensitive cell lines; 2) analysis of genomic instability associated with interruption of DNA synthesis; and 3) correlation of the temporal development of karyotypic (molecular biologic) alterations with specific biologic properties of drug resistant cells. We are hopeful that by combining chromosomal analysis with modern molecular and cellular biologic techniques, this research may provide a significant lead in understanding mechanisms of acquired drug resistance of direct relevance to clinical oncology.